Document Detail


Superoxide dismutase restores eNOS expression and function in resistance pulmonary arteries from neonatal lambs with persistent pulmonary hypertension.
MedLine Citation:
PMID:  18790993     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Endothelial nitric oxide (NO) synthase (eNOS) expression and activity are decreased in fetal lambs with persistent pulmonary hypertension (PPHN). We sought to determine the impact of mechanical ventilation with O(2) with or without inhaled NO (iNO) or recombinant human SOD (rhSOD) on eNOS in the ductal ligation model of PPHN. PPHN lambs and age-matched controls were ventilated with 100% O(2) for 24 h alone or combined with 20 ppm iNO continuously or a single dose of rhSOD (5 mg/kg) given intratracheally at delivery. In 1-day spontaneously breathing lambs, eNOS expression in resistance pulmonary arteries increased relative to fetal levels. eNOS expression increased in control lambs ventilated with 100% O(2), but not in PPHN lambs. Addition of iNO or rhSOD increased eNOS expression and decreased generation of reactive oxygen species (ROS) in PPHN lambs relative to those ventilated with 100% O(2) alone. However, only rhSOD restored eNOS function, increased tetrahydrobiopterin (BH(4)), a critical cofactor for eNOS function, and restored GTP cyclohydrolase I expression in isolated vessels and lungs from PPHN lambs. These data suggest that ventilation of PPHN lambs with 100% O(2) increases ROS production, blunts postnatal increases in eNOS expression, and decreases available BH(4) in PPHN lambs. Although the addition of iNO or rhSOD diminished ROS production and increased eNOS expression, only rhSOD improved eNOS function and levels of available BH(4). Thus therapies designed to decrease oxidative stress and restore eNOS coupling, such as rhSOD, may prove useful in the treatment of PPHN in newborn infants.
Authors:
Kathryn N Farrow; Satyan Lakshminrusimha; William J Reda; Stephen Wedgwood; Lyubov Czech; Sylvia F Gugino; Jonathan M Davis; James A Russell; Robin H Steinhorn
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Publication Detail:
Type:  Editorial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-09-12
Journal Detail:
Title:  American journal of physiology. Lung cellular and molecular physiology     Volume:  295     ISSN:  1040-0605     ISO Abbreviation:  Am. J. Physiol. Lung Cell Mol. Physiol.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-12-02     Completed Date:  2009-01-22     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L979-87     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Animals, Newborn
Biopterin / analogs & derivatives,  biosynthesis
GTP Cyclohydrolase / biosynthesis
Gene Expression Regulation, Enzymologic / drug effects*
Humans
Infant, Newborn
Lung / enzymology*
Nitric Oxide / metabolism
Nitric Oxide Synthase Type III / biosynthesis*
Oxidative Stress / drug effects
Persistent Fetal Circulation Syndrome / drug therapy*,  enzymology
Pulmonary Artery / enzymology*
Reactive Oxygen Species / metabolism
Recombinant Proteins / pharmacology
Respiration, Artificial
Sheep
Superoxide Dismutase / pharmacology*
Grant Support
ID/Acronym/Agency:
HL-086715/HL/NHLBI NIH HHS; HL-54705/HL/NHLBI NIH HHS; K08 HL086715/HL/NHLBI NIH HHS; R01 HL054705/HL/NHLBI NIH HHS; R01 HL054705-12/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Reactive Oxygen Species; 0/Recombinant Proteins; 17528-72-2/5,6,7,8-tetrahydrobiopterin; 22150-76-1/Biopterin; 31C4KY9ESH/Nitric Oxide; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 1.15.1.1/Superoxide Dismutase; EC 3.5.4.16/GTP Cyclohydrolase
Comments/Corrections

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